RESUMO
BACKGROUND: While B-cells have historically been implicated in allergy development, a growing body of evidence supports their role in atopic dermatitis (AD). B-cell differentiation across ages in AD, and its relation to disease severity scores, has not been well defined. OBJECTIVE: To compare the frequency of B-cell subsets in blood of 0-5, 6-11, 12-17, and ≥18 years old patients with AD versus age-matched controls. METHODS: Flow cytometry was used to measure B-cell subset frequencies in the blood of 27 infants, 17 children, 11 adolescents, and 31 adults with moderate-to-severe AD and age-matched controls. IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometry panel were used to determine frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgEs) levels were measured using ImmunoCAP®. RESULTS: Adolescents with AD had lower frequencies of major B-cells subsets (p < .03). CD23 expression increased with age and was higher in AD compared to controls across all age groups (p < .04). In AD patients, multiple positive correlations were observed between IL-17-producing T-cells and B-cell subsets, most significantly non-switched memory (NSM) B-cells (r = .41, p = .0005). AD severity positively correlated with a list of B-cell subsets (p < .05). IL-9 levels gradually increased during childhood, reaching a peak in adolescence, paralleling allergen sensitization, particularly in severe AD. Principal component analysis of the aggregated environmental sIgE data showed that while controls across all ages tightly clustered together, adolescents with AD demonstrated distinct clustering patterns relative to controls. CONCLUSIONS: Multiple correlations between B-cells and T-cells, as well as disease severity measures, suggest a complex interplay of immune pathways in AD. Unique B-cell signature during adolescence, with concurrent allergen sensitization and IL-9 surge, point to a potentially wider window of opportunity to implement interventions that may prevent the progression of the atopic march.
RESUMO
PURPOSE: To develop the PROMIS Pediatric Stigma (PPS) and Skin (PPS-Skin) by constructing a common metric for measuring stigma in children with various conditions, while capturing the unique features of each condition. METHODS: Data from 860 children, ages 8-17, with a diagnosis of epilepsy, pNF (neurofibromatosis type 1 associated neurofibroma plexform), MD (muscular dystrophy), cancer, or skin conditions recruited from three projects were analyzed. Children with epilepsy, pNF and MD (sample-1) completed the original 18-item Neuro-QoL Stigma, while children with cancer and skin conditions (e.g., atopic dermatitis, psoriasis, and genetic skin disorders; sample-2) completed a 16-item version and 6 additional skin related items. Exploratory factor analysis (EFA) and confirmatory analysis (CFA) were used to evaluate unidimensionality of 24 stigma items. Differential item functioning (DIF) was used to evaluate measurement equivalence on group, gender, age, and conditions. Item response theory model (IRT) was used to construct the final measure. RESULTS: Sufficient unidimensionality was supported by both EFA and CFA. No items showed significant DIF indicating stable measurement properties across groups of comparison. All items fit the IRT model and were able to be calibrated together to form the PPS which consists of 18 core items. The PPS-Skin (18 cores items + 6 skin items) was developed by calibrating 6 skin items onto the common metric as the PPS. CONCLUSIONS: We used IRT techniques to successfully develop the PPS and the PPS-Skin, which share a common metric and account for unique and common concerns related to chronic conditions.
Assuntos
Epilepsia , Neoplasias , Humanos , Criança , Qualidade de Vida/psicologia , Inquéritos e Questionários , Doença Crônica , Psicometria/métodosRESUMO
BACKGROUND: Patients with atopic dermatitis (AD) have systemic biomarker dysregulation that differs by age group; however, the proteomic characteristics of these age-based changes are unknown. OBJECTIVE: To profile blood proteins of patients with AD across different age groups versus age-appropriate controls. METHODS: Using the Olink high-throughput proteomic platform, we profiled 375 serum proteins of 20 infants (age, 0-5 years), 39 children (age, 6-11 years), 21 adolescents (age, 12-17 years), and 20 adults (age, ≥18 years) with moderate-to-severe AD and 83 age-appropriate controls. RESULTS: Each group presented a distinct systemic proteomic signature. Th2-related proteins were increased in infant AD and further intensified with age through adolescence and adulthood (interleukin 4/CCL13/CCL17). In contrast, Th1 axis down-regulation was detected in infants with AD and gradually reversed to increased Th1 products (interferon γ/CXCL9/CXCL10/CCL2) in patients with AD from childhood to adulthood. Despite their short disease duration, infants already had evidence of systemic inflammation, with significant upregulation of innate immunity (interleukin 17C/ interleukin-1RN), T-cell activation/migration (CCL19), Th2 (CCL13/CCL17), and Th17 (PI3) proteins. Adults with AD present unique upregulation of cardiovascular proteins related to coagulation and diabetes. LIMITATIONS: Cross-sectional observational study with a single time point. CONCLUSION: Systemic immune signatures of AD are age-specific beyond the shared Th2 immune activation. These data advocate for precision medicine approaches based on age-specific AD profiles.
Assuntos
Dermatite Atópica , Adulto , Criança , Adolescente , Humanos , Lactente , Adulto Jovem , Recém-Nascido , Pré-Escolar , Proteômica , Estudos Transversais , Inflamação , Proteínas , Células Th2RESUMO
BACKGROUND: Fatigue is a symptom that can negatively impact patients' quality of life. However, the relationship of AD with fatigue has not been fully studied, especially in children. OBJECTIVE: To determine the prevalence of fatigue in AD patients, and whether AD severity, demographics and comorbidities are associated with increased fatigue in children. METHODS: A cross-sectional observational study was performed among 248 children with AD. Paediatric patients (ages 8-17 years) and parents (of children ages 0-17 years) completed a questionnaire, including demographics, history of atopic comorbidities and validated severity measures of AD, itch, pain, sleep disturbance, sleep-related impairment and fatigue. AD severity was also assessed by clinician-reported Eczema Area and Severity Index (EASI), Scoring AD (SCORAD) and Investigator's Global Assessment (IGA). Fatigue was assessed using Patient Reported Outcome Measurement Information System (PROMIS) Pediatric Fatigue T-score. RESULTS: Most children with AD had no (38.6%) or mild (32.1%) fatigue, with fewer having moderate (27.2%) or severe (2%) fatigue. Moderate/severe PROMIS Pediatric fatigue T-scores were increased with moderate (25.7%/1.4%) and severe (39.3%/5.4%) IGA vs. mild IGA (18.0%/0.0%) and those with 5-6 (44.4%/0.0%) and 7 (44.2%/5.2%) nights of SD from eczema. Moderate-severe PROMIS Pediatric Fatigue T-scores were associated with history of hay fever (adjusted OR [95% Cl]: 2.803 [1.395-5.632]) and family income (<$100,000: 3.049 [1.294-7.181]), but inversely with Black (0.40 [0.168-0.969]) and AAPI (0.285 [0.094-0.859]) race. In multivariable regression models controlling for demographic factors, PROMIS Pediatric Fatigue T-score was significant with more severe scores for IGA, POEM, EASI, SCORAD, NRS-itch, SCORAD-itch, average itch in the past 7 days, PROMIS Pediatric Pain severity, PROMIS Pediatric SD, PROMIS Pediatric SRI, SCORAD-sleep and more frequent SD from AD. CONCLUSIONS: Fatigue is a common yet underappreciated symptom in children with AD, particularly those with moderate-severe AD, and warrants more attention in clinical practice and trials.
Assuntos
Dermatite Atópica , Eczema , Humanos , Criança , Adolescente , Recém-Nascido , Lactente , Pré-Escolar , Dermatite Atópica/complicações , Dermatite Atópica/epidemiologia , Dermatite Atópica/diagnóstico , Estudos Transversais , Qualidade de Vida , Prevalência , Índice de Gravidade de Doença , Eczema/complicações , Prurido/etiologia , Prurido/complicações , Fadiga/epidemiologia , Fadiga/etiologia , Imunoglobulina ARESUMO
BACKGROUND: Race and socioeconomic status are thought to influence the severity of atopic dermatitis (AD), but findings differ between countries and measures used. The role of social determinants of health versus biologic factors in causing these differences is poorly understood. OBJECTIVE: We hypothesized that spatially-derived factors correlate with AD severity and patient-reported outcome (PRO) in a pediatric cohort from Chicago, USA. METHODS: Children with AD and caregivers were enrolled from February 2018 to April 2019 in this single-site cross-sectional study. Severity was self- and physician-assessed using validated measures. Patient addresses were geocoded and linked to census tract IDs. Deprivation index (DI) was calculated using variables of the 2018 American Community Survey. RESULTS: Among 216 children aged 5-17 years old, 111 (51.4%) lived in urban, 104 (48.1%) suburban, and one (0.5%) in rural areas. Race was self-classified as White in 31.0%, Black 24.5%, other or mixed 25.0%, and Asian 19.4%; 24.5% were Hispanic. Median DI was 0.32 (range 0.03-0.72), with higher scores indicating more deprivation. DI correlated with insurance type, family income, ethnicity, race, and parental education, and weakly with selected PRO T-scores. However, no correlations between any AD severity score and DI, race, ethnicity, income, education, or insurance type were found. CONCLUSION: The impact of socioeconomic factors on AD severity in our study population was less pronounced than expected. This could be because of regional differences, including access to high-quality care. The role of access as a deciding factor in the impact of socioeconomic status on AD outcome deserves further investigation.
Assuntos
Dermatite Atópica , Fatores Socioeconômicos , Adolescente , Criança , Pré-Escolar , Humanos , Estudos Transversais , Dermatite Atópica/epidemiologia , EtnicidadeRESUMO
BACKGROUND/OBJECTIVES: Healthcare transition (HCT) refers to movement from pediatric to adult healthcare models. Lack of HCT preparation contributes to poor health outcomes. This study measures readiness to transition in individuals with genetic skin conditions. METHODS: Participants signed IRB-approved consents/assents. Participants ages 14-22 years with genetic skin disorders were surveyed with measures of QoL (Children's Dermatology Life Quality Index/CDLQI or DLQI) and HCT readiness using the Transition Readiness Assessment Questionnaire (TRAQ) and adapted non-validated measures of Skin Knowledge and Psychosocial Factors (5 = highest readiness). Mean TRAQ was compared with historical data on controls and other chronic conditions (t-tests) and correlated (Pearson) with Skin Knowledge and Psychosocial. Multivariable regression compared demographics and QoL with transition readiness. RESULTS: A total of 45 participants were enrolled (mean age 17.8 years, 67% female, 71% White; disorders of cornification [n = 31], ectodermal dysplasias [n = 7], epidermolysis bullosa [n = 4], tuberous sclerosis [n = 3]). Mean TRAQ (3.3 ± 0.9) was lower than controls (3.9; p < .001) and some chronic disorders (sickle cell [3.7; p < .05], type 1 diabetes [3.7; p < .01]), but higher than with spina bifida (2.8; p < .001) and congenital heart disease (2.9; p < .01). Mean Skin Knowledge was 4.2 ± 1.0, and mean Psychosocial was 3.4 ± 0.8. TRAQ correlated strongly with Skin Knowledge (r = .61; p < .05), but not Psychosocial (r = .12; p = .6). Ages 14-17 years versus 18-22 years and public versus private insurance predicted lower TRAQ scores. Poor DLQI predicted higher TRAQ and Skin Knowledge, but poor DLQI and CDLQI predicted lower Psychosocial. CONCLUSIONS: Adolescents and young adults with genetic skin disorders demonstrated low transition readiness, especially among younger-aged and lower socioeconomic groups. We recommend a HCT intervention to improve health outcomes.
Assuntos
Dermatopatias , Transição para Assistência do Adulto , Humanos , Adolescente , Feminino , Adulto Jovem , Criança , Idoso , Masculino , Qualidade de Vida , Inquéritos e Questionários , Dermatopatias/terapia , Doença CrônicaRESUMO
BACKGROUND: The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored. OBJECTIVES: To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes. METHODS: Body site-matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis. RESULTS: Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes. CONCLUSIONS: The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic? The skin microbiome of congenital ichthyoses is largely unexplored. Microbes play an important role in pathogenesis, as infections are common. The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add? A common skin microbiome signature was observed across congenital ichthyoses. Distinct microbiome features were associated with ichthyosis subtypes. Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message? These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention.
Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Microbiota , Adulto , Humanos , Ictiose/genética , Ictiose Lamelar/genética , Lipídeos , Microbiota/genética , Pele/patologiaRESUMO
BACKGROUND: Skin biopsies promote our understanding of atopic dermatitis/AD pathomechanisms in infants/toddlers with early-onset AD, but are not feasible in pediatric populations. Tape strips are an emerging, minimally invasive alternative, but global transcriptomic profiling in early pediatric AD is lacking. We aimed to provide global lesional and nonlesional skin profiles of infants/toddlers with recent-onset, moderate-to-severe AD using tape strips. METHODS: Sixteen tape strips were collected for RNA-seq profiling from 19 infants/toddlers (<5 years old; lesional and nonlesional) with early-onset moderate-to-severe AD (≤6 months) and 17 healthy controls. RESULTS: We identified 1829 differentially expressed genes/DEGs in lesional AD and 662 DEGs in nonlesional AD, vs healthy skin (fold-change ≥2, FDR <0.05), with 100% sample recovery. Both lesional and nonlesional skin showed significant dysregulations of Th2 (CCL17 and IL4R) and Th22/Th17 (IL36G, CCL20, and S100As)-related genes, largely lacking significant Th1-skewing. Significant down-regulation of terminal differentiation (FLG and FLG2), lipid synthesis/metabolism (ELOVL3 and FA2H), and tight junction (CLDN8) genes were primarily seen in lesional AD. Significant negative correlations were identified between Th2 measures and epidermal barrier gene-subsets and individual genes (FLG with IL-4R and CCL17; r < -0.4, P < .05). Significant correlations were also identified between clinical measures (body surface area/BSA, pruritus ADQ, and transepidermal water loss/TEWL) with immune and barrier mRNAs in lesional and/or nonlesional AD (FLG/FLG2 with TEWL; r < -0.4, P < .05). CONCLUSION: RNA-seq profiling using tape strips in early-onset pediatric AD captures immune and barrier alterations in both lesional and nonlesional skin. Tape strips provide insight into disease pathomechanisms and cutaneous disease activity.
Assuntos
Dermatite Atópica , Eczema , Criança , Pré-Escolar , Dermatite Atópica/genética , Epiderme , Proteínas Filagrinas , Perfilação da Expressão Gênica , Humanos , PeleRESUMO
BACKGROUND: The distribution of pediatric-onset morphea and site-based likelihood for extracutaneous complications has not been well characterized. OBJECTIVE: To characterize the lesional distribution of pediatric-onset morphea and to determine the sites with the highest association of extracutaneous manifestations. METHODS: A retrospective cross-sectional study was performed. Using clinical photographs, morphea lesions were mapped onto body diagrams using customized software. RESULTS: A total of 823 patients with 2522 lesions were included. Lesions were more frequent on the superior (vs inferior) anterior aspect of the head and extensor (vs flexor) extremities. Linear morphea lesions were more likely on the head and neck, whereas plaque and generalized morphea lesions were more likely on the trunk. Musculoskeletal complications were more likely with lesions on the extensor (vs flexor) extremity (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.4), whereas neurologic manifestations were more likely with lesions on the anterior (vs posterior) (OR, 2.8; 95% CI, 1.7-4.6) and superior (vs inferior) aspect of the head (OR, 2.3; 95% CI, 1.6-3.4). LIMITATIONS: Retrospective nature and the inclusion of only patients with clinical photographs. CONCLUSION: The distribution of pediatric-onset morphea is not random and varies with body site and within individual body sites. The risk stratification of extracutaneous manifestations by body site may inform decisions about screening for extracutaneous manifestations, although prospective studies are needed.
Assuntos
Transtornos da Cefaleia/epidemiologia , Doenças Musculoesqueléticas/epidemiologia , Esclerodermia Localizada/epidemiologia , Convulsões/epidemiologia , Idade de Início , Criança , Pré-Escolar , Estudos Transversais , Eletroencefalografia/estatística & dados numéricos , Feminino , Transtornos da Cefaleia/diagnóstico , Transtornos da Cefaleia/etiologia , Humanos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Doenças Musculoesqueléticas/diagnóstico , Doenças Musculoesqueléticas/etiologia , Fotografação , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Esclerodermia Localizada/complicações , Esclerodermia Localizada/diagnóstico , Convulsões/diagnóstico , Convulsões/etiologia , Pele/diagnóstico por imagemRESUMO
BACKGROUND: Accurately documenting pediatric atopic dermatitis (AD) severity is important, but research tools, such as Eczema Area and Severity Index (EASI), are too time consuming for clinical settings. Product of the Physician Global Assessment and affected percentage of body surface area (PGA×BSA) is a new, rapid measure of psoriasis severity. OBJECTIVE: To evaluate an Investigator Global Assessment and body surface area product (IGA×BSA) as an easy-to-use severity measure for pediatric AD. METHODS: Patient-reported and objective disease severity measures were collected from 195 caretaker/child dyads (child age range, 5-17 years) with almost clear (Validated Investigator Global Assessment for AD [vIGA] of 1) to severe (vIGA of 4) AD. Data were assessed with Spearman coefficients and plots. Severity strata were proposed by using an anchoring approach based on the EASI. RESULTS: IGA×BSA correlates better with the EASI than IGA alone (r = 0.924 vs r = 0.757, P < .001). Bland-Altman plot indicates high and consistent agreement between IGA×BSA and the EASI. Suggested severity strata for IGA×BSA are 0-30, mild; 30.1-130, moderate; and 130.1-400, severe (κ = 0.760). LIMITATIONS: The patient cohort was predominantly from the midwestern United States. CONCLUSIONS: IGA×BSA (using the vIGA) is a simple measure that correlates well with the EASI in patients with mild to severe pediatric AD. Future work is needed to affirm reliability across IGA scales and responsiveness to change.
Assuntos
Dermatite Atópica/diagnóstico , Índice de Gravidade de Doença , Adolescente , Fatores Etários , Superfície Corporal , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Meio-Oeste dos Estados Unidos , Medidas de Resultados Relatados pelo Paciente , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Transepidermal water loss (TEWL) is a surrogate measure of skin barrier dysfunction. Historically, devices that measure TEWL are expensive, complex, and require connection to a computer and energy source. Consequently, measurement of skin's TEWL has been limited to the research setting. OBJECTIVES: Evaluate the accuracy of the handheld device gpskin Barrier Light® in comparison with a standardly used device, AquaFlux AF200® , for measuring TEWL. METHODS: Transepidermal water loss measurements by gpskin Barrier Light® and AquaFlux AF200® in ichthyotic and healthy skin were compared. RESULTS: AquaFlux AF200® TEWL readings were consistently higher than those from gpskin Barrier Light® . In the pooled cohort, TEWL values were strongly correlated and both devices had excellent reliability. When subjects and controls were examined separately, there was moderate correlation between devices, with stronger agreement at higher TEWL values. LIMITATIONS: Transepidermal water loss was determined at one time point. There is no formally established industry standard TEWL-assessing device. CONCLUSION: Although gpskin Barrier Light® and AquaFlux AF200® devices cannot be used interchangeably, correlation in measuring TEWL was strong in patients with skin disease. This finding suggests that the low-cost, handheld device can accurately capture change in TEWL to track disease improvement.
Assuntos
Ictiose , Perda Insensível de Água , Humanos , Reprodutibilidade dos Testes , Pele/metabolismo , Água/metabolismoRESUMO
As a surrogate measure of skin barrier dysfunction, we sought to determine differences in transepidermal water loss (TEWL) among ichthyosis subtypes and correlate TEWL with clinical severity. Subjects with Netherton syndrome had the highest TEWL values (increased water loss), while TEWL values were lowest in subjects with epidermolytic ichthyosis. TEWL correlated with severity only in lamellar ichthyosis and age was inversely correlated with TEWL (rs = -.213, P = .02). TEWL is an objective measure that complements disease severity in ichthyosis and may be used as an adjuvant to monitor treatment response.
Assuntos
Ictiose Lamelar , Ictiose , Síndrome de Netherton , Humanos , Ictiose Lamelar/diagnóstico , Ictiose Lamelar/genética , Água , Perda Insensível de ÁguaRESUMO
Vitiligo is characterized by progressive loss of skin pigmentation. The search for aetiologic factors has led to the biochemical, the neurologic and the autoimmune theory. The convergence theory was then proposed several years ago to incorporate existing theories of vitiligo development into a single overview of vitiligo aetiology. The viewpoint that vitiligo is not caused only by predisposing mutations, or only by melanocytes responding to chemical/radiation exposure, or only by hyperreactive T cells, but rather results from a combination of aetiologic factors that impact melanocyte viability, has certainly stood the test of time. New findings have since informed the description of progressive depigmentation. Understanding the relative importance of such aetiologic factors combined with a careful selection of the most targetable pathways will continue to drive the next phase in vitiligo research: the development of effective therapeutics. In that arena, it is likewise important to acknowledge that pathways affected in some patients may not be altered in others. Taken together, the convergence theory continues to provide a comprehensive viewpoint of vitiligo aetiology. The theory serves to intertwine aetiologic pathways and will help to define pathways amenable to disease intervention in individual patients.
Assuntos
Vitiligo/etiologia , Humanos , Melanócitos/fisiologiaRESUMO
BACKGROUND: Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD. OBJECTIVE: To analyze blood inflammatory proteins of early pediatric AD. METHODS: Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD. RESULTS: In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11). LIMITATIONS: Different baseline expression levels in healthy pediatric vs adult samples. CONCLUSIONS: Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.
Assuntos
Quimiocinas/sangue , Dermatite Atópica/sangue , Elafina/sangue , Inflamação/sangue , Metaloproteinases da Matriz/sangue , Receptores de Interleucina/sangue , Fatores Etários , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Doença Crônica , Dermatite Atópica/metabolismo , Selectina E/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Lactente , Subunidade alfa de Receptor de Interleucina-2/sangue , Masculino , Peroxidase/sangue , Proteoma/metabolismo , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Fator de Crescimento Transformador alfa/sangueRESUMO
Hospital-acquired pneumonia is associated with high rates of morbidity and mortality, and dissemination to the bloodstream is a recognized risk factor for particularly poor outcomes. Yet the mechanism by which bacteria in the lungs gain access to the bloodstream remains poorly understood. In this study, we used a mouse model of Pseudomonas aeruginosa pneumonia to examine this mechanism. P. aeruginosa uses a type III secretion system to deliver effector proteins such as ExoS directly into the cytosol of eukaryotic cells. ExoS, a bi-functional GTPase activating protein (GAP) and ADP-ribosyltransferase (ADPRT), inhibits phagocytosis during pneumonia but has also been linked to a higher incidence of dissemination to the bloodstream. We used a novel imaging methodology to identify ExoS intoxicated cells during pneumonia and found that ExoS is injected into not only leukocytes but also epithelial cells. Phagocytic cells, primarily neutrophils, were targeted for injection with ExoS early during infection, but type I pneumocytes became increasingly injected at later time points. Interestingly, injection of these pneumocytes did not occur randomly but rather in discrete regions, which we designate ""fields of cell injection" (FOCI). These FOCI increased in size as the infection progressed and contained dead type I pneumocytes. Both of these phenotypes were attenuated in infections caused by bacteria secreting ADPRT-deficient ExoS, indicating that FOCI growth and type I pneumocyte death were dependent on the ADPRT activity of ExoS. During the course of infection, increased FOCI size was associated with enhanced disruption of the pulmonary-vascular barrier and increased bacterial dissemination into the blood, both of which were also dependent on the ADPRT activity of ExoS. We conclude that the ADPRT activity of ExoS acts upon type I pneumocytes to disrupt the pulmonary-vascular barrier during P. aeruginosa pneumonia, leading to bacterial dissemination.
Assuntos
ADP Ribose Transferases/metabolismo , Bacteriemia/patologia , Toxinas Bacterianas/metabolismo , Pneumonia Bacteriana/patologia , Infecções por Pseudomonas/patologia , Animais , Bacteriemia/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Citometria de Fluxo , Doença Iatrogênica , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia Bacteriana/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosaRESUMO
Many bacterial pathogens have evolved ingenious ways to escape from the lung during pneumonia to cause bacteremia. Unfortunately, the clinical consequences of this spread to the bloodstream are frequently dire. It is therefore important to understand the molecular mechanisms used by pathogens to breach the lung barrier. We have recently shown that Pseudomonas aeruginosa, one of the leading causes of hospital-acquired pneumonia, utilizes the type III secretion system effector ExoS to intoxicate pulmonary epithelial cells. Injection of these cells leads to localized disruption of the pulmonary-vascular barrier and dissemination of P. aeruginosa to the bloodstream. We put these data in the context of previous studies to provide a holistic model of P. aeruginosa dissemination from the lung. Finally, we compare P. aeruginosa dissemination to that of other bacteria to highlight the complexity of bacterial pneumonia. Although respiratory pathogens use distinct and intricate strategies to escape from the lungs, a thorough understanding of these processes can lay the foundation for new therapeutic approaches for bacterial pneumonia.